Tetrazole derivatives

ABSTRACT

The present invention is directed to a tetrazole derivative represented by the following formula (1) or a salt thereof: ##STR1## wherein R 1  and R 2  independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkanoyloxy group; R 3  represents a hydrogen atom or a substituted or unsubstituted lower alkyl group; A represents a methyleneoxy group or a vinylene group; Z represents a substituted or unsubstituted benzimidazolyl group; and a broken line indicates that there may be a double bond; and to a medicine containing the compound as an active ingredient. The medicine according to the present invention is endowed with excellent antileukotriene activity and antihistaminic activity, and is useful for the prevention and treatment of, for example, asthma.

This application is a Divisional of U.S. application Ser. No.09/158,744, filed on Sep. 23, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a tetrazole derivative and saltsthereof, which have excellent antileukotriene activity andantihistaminic activity and are useful as a medicine for a broad rangeof allergic diseases.

2. Background Art

Leukotrienes (LTs) participate in most inflammatory diseases, includingasthma, psoriasis, rheumatism, and inflammatory colitis, and play animportant role in inflammation caused by cytotoxic reactions.

Thus, on the basis of the finding that leukotrienes are predominantmediators in allergic reactions and inflammations, there have beendiscovered, in an attempt to relieve these pathological conditions, annumber of substances that suppress the action or the synthesis ofleukotrienes (S. T. Holgate et al.: J. Allergy Clin. Immunol. 98, 1-13(1996)).

Leukotrienes are arachidonic acid metabolites synthesized by5-lipoxygenase (5-LO) and are divided into two groups. One group refersto LTB₄ and exhibits strong chemotaxis towards leukocytes. The othergroup collectively encompasses cysteine leukotrienes (CysLTs), includingLTC₄, LTD₄, and LTE₄ ; these substances have long been called"slow-reacting substances of anaphylaxis (SRS-A)." In human tissues,CysLTs exert actions when they are coupled with their receptors. It hasbeen found that a selective LTD₄ receptor inhibitor suppresses thecontracting action of both LTC₄ and LTD₄ in human lung tissue,suggesting that the binding site of an LTD₄ receptor for LTD₄ alsoserves as a binding site for LTC₄ (Buckner C. K. et al.: Ann. NY Acad.Sci. 1988, 524; 181-6, Aharony D. et al.: New Trends in Lipid MediatorsResearch, Basel: Karger 1989; 67-71). LTE₄ is also considered to exertits action by the mediation of the same receptor available for LTD₄.However, since its activity is low, LTE₄ is considered a partiallyactive substance.

Meanwhile, histamine contracts bronchial smooth muscle and promotescapillary permeability when coupled to an H₁ receptor prevailing in thecell membrane, and thus is considered a significant mediator in allergicdiseases. More specifically, histamine is considered to triggeraggravation of various symptoms of asthma due to its bronchialcontracting action, and is also considered to increase leakage of bloodcomponents into intercellular space due to its capillary permeationpromotion action, to thereby participate in the onset mechanism ofallergic rhinitis and the formation of edema in conjunctivitis, etc.Antihistaminic agents have been used in the treatment of allergicdiseases as mentioned above. However, conventional antihistaminic agentsinvolve the fear of causing adverse side effects to the central nervoussystem, such as drowsiness, when such an agent is coupled to an H₁receptor in the brain. In recent years, bronchial asthma has beenconsidered a chronic airway inflammation in which eosinocytesparticipate. In this connection, attention has been drawn to a delayedresponse which manifests airway constriction unique to asthma, as aresult of infiltration of inflammation cells into bronchial mucosa andhypersecretion from the mucosa.

Briefly, in allergic diseases such as asthma, pathological profiles ofimmediate asthma response--i.e., bronchoconstriction and formation ofedema in which histamine and similar mediators participate--and those oflate asthma response--i.e., airway constriction that results fromcellular infiltration, mucous secretion, hyperplasia of membrane, etc.in which leukotrienes participate--are deemed to play a significant rolein the manifestation of pathological conditions. Similarly, thepathological profile of allergic rhinitis also comes to be elucidated asa two-phase reaction including an immediate asthma response phasemanifesting ptarmus and hypersecretion of pituita, and a late asthmaresponse phase manifesting nasal congestion due to swelling of the nasalmembrane; wherein histamine participates in the former and leukotrieneparticipates in the latter.

Accordingly, it is considered that a compound which exhibits antagonismagainst both a histamine H₁ receptor and an LTD₄ receptor and whichminimally migrates into the brain can serve as a medicine having reducedside effects and can be effective for the prevention and treatment of avariety of symptoms from the instant response phase to the delayedresponse phase of a broad range of allergic diseases; in particular,asthma and rhinitis.

However, until realization of the present invention, a compoundexhibiting sufficient antagonism against both the LTD₄ receptor--whichrelates to the late asthma response phase--and the histamine H₁receptor--which relates to the immediate asthma response phase--had notyet been found. Moreover, many LTD₄ antagonists which are now beingdeveloped have at least one acid group in the molecule and arehydrophilic compounds having high polarity; inevitably they are notsufficiently absorbed by the oral route, leading to an increase in doseof these types of drugs and causing side effects.

SUMMARY OF THE INVENTION

In view of the foregoing, the present inventors have conducted extensivestudies in search of a compound which has both anti-leukotriene activityand antihistaminic activity and which does not have the aforementioneddrawbacks, and have found that the compound represented by the followingformula (1) satisfactorily meets the present purposes, to therebycomplete the present invention.

Accordingly, an object of the present invention is to provide an novelcompound which has antihistaminic activity and anti-leukotrieneactivity, which minimally migrates into the brain, and which has no acidgroup in the molecule.

In one aspect of the present invention, there is provided a tetrazolederivative or a salt thereof represented by the following formula (1):##STR2## wherein R¹ and R² independently represent a hydrogen atom, ahydroxyl group, a lower alkyl group, a substituted or unsubstitutedalkoxy group, or a substituted or unsubstituted alkanoyloxy group; R³represents a hydrogen atom or a substituted or unsubstituted lower alkylgroup; A represents a methyleneoxy group or a vinylene group; Zrepresents a substituted or unsubstituted quinolyl group, a substitutedor unsubstituted quinazolyl group, or a substituted or unsubstitutedbenzimidazolyl group; and a broken line indicates that there may be adouble bond.

In another aspect of the present invention, there is provided a medicinecomprising as an active ingredient a tetrazole derivative represented bythe above-described formula (1) or a salt thereof.

In still another aspect of the present invention, there is provided apharmaceutical composition comprising a tetrazole derivative representedby the above-described formula (1) or a salt thereof, and apharmacologically acceptable carrier.

In yet another aspect of the present invention, there is provided use,as a medicine, of a tetrazole derivative represented by theabove-described formula (1) or a salt thereof.

In yet another aspect of the present invention, there is provided amethod for the treatment of allergic diseases, which method comprisesadministering to a patient in need thereof an effective amount of atetrazole derivative represented by the above-described formula (1) or asalt thereof.

In yet another object of the present invention, there is provided amethod for the treatment of a disease selected from the group consistingof asthma, allergic rhinitis, allergic conjunctivitis, atopicdermatitis, urticaria, psoriasis, rheumatism, inflammatory colitis,cerebral ischemia, and cerebral apoplexy, which method comprisesadministering to a patient in need thereof an effective amount of atetrazole derivative represented by the above-described formula (1) or asalt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the tetrazole derivative of formula (1), the lower alkyl groupsrepresented by R¹ or R² include C1-C6 linear or branched alkyl groups.Specific examples thereof include a methyl group, an ethyl group, an-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, asec-butyl group, a t-butyl group, a pentyl group, and a hexyl group. Ofthese groups, a methyl group and a t-butyl group are particularlypreferred. The alkoxy group may be linear or branched and may have 1-6carbon atoms. Examples of preferred alkoxy groups include a methoxygroup, an ethoxy group, a n-propoxy group, an i-propoxy group, a butoxygroup, a pentyloxy group, and a hexyloxy group. Of these, a methoxygroup, an ethoxy group and a n-propoxy group are particularly preferred.The alkoxy groups may have substituents. Examples of the substituentsinclude an alkoxy group; a halogen atom; a phenyl group which may have asubstituent such as a quinolyl methoxy group; a piperazinyl group whichmay have a substituent such as a methyl group or a quinolylmethyl group;and a di-(C1-C4)alkylamino group such as a dimethylamino group or adiethylamino group. The alkanoyloxy group preferably has 2 to 5 carbonatoms; for example, mention may be given of an acetyloxy group, apropionyloxy group, and an n-butylyloxy group. The alkanoyloxy group mayhave a substituent such as an amino group.

In the formula, the lower alkyl groups represented by R³ include C1-C6linear or branched alkyl groups. Specific examples thereof include amethyl group, an ethyl group, an n-propyl group, an i-propyl group, an-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, apentyl group, and a hexyl group. Of these groups, a methyl group isparticularly preferred. The lower alkyl groups may have substituents.Examples of the substituents include a halogen atom, an amino group, aphenyl group, and a heterocyclic group such as a piperazinyl group.These substituents may further have substituents such as a C1-C4 alkylgroup, e.g., methyl or ethyl; a quinolyl C1-C4 alkoxy group, e.g., aquinolyl methoxy group; a benzimidazolyl C1-C4 alkoxy group, e.g., abenzimidazolyl methoxy group; or a quinolyl C1-C4 alkyl group, e.g., aquinolyl methyl group. Preferably, R³ is a hydrogen atom, a methylgroup, a dimethylaminomethyl group, or a3-[4-(2-quinolylmethyl)piperazinyl]propyl group.

Examples of groups represented by Z include a quinolyl group, aquinazolyl group, and a benzimidazolyl group; these groups may havesubstituents. Examples of the substituents include a C1-C4 alkyl group,e.g., a methyl group or an ethyl group; and a (C1-C4)alkoxy(C1-C4)alkylgroup, e.g., an ethoxyethyl group or a methoxymethyl group.

No particular limitation is imposed on the salts of the compounds of thepresent invention represented by formula (1), so long as they arepharmacologically acceptable. Examples of such salts include acidaddition salts of mineral acids, such as hydrochlorides, hydrobromides,hydroiodides, sulfates, and phosphates; and acid addition salts oforganic acids, such as benzoates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarates,tartarates and citrates.

The compound of formula (1) of the present invention (hereinafter may bereferred to as compound (1)) may take the form of a solvate such as ahydrate, and the present invention encompasses such a solvate.

Also, the compound (1) may take the form of a ketoenol tautomer, and thepresent invention encompasses such a tautomer.

The compound (1) of the present invention may be prepared by, forexample, the methods described below. ##STR3## wherein X represents ahalogen atom, and R¹, R², A, and B have the same meanings as describedabove.

Briefly, the compound (1a) of the present invention in which R¹ and R²independently represent a hydrogen atom, a hydroxyl group, a lower alkylgroup, or a lower alkoxyl group may be prepared, as shown in Method A,by causing a reaction between a tetrazolylquinolinone compound (2) and ahalogen compound (3) in an amount of one equivalent, in the presence ofan excessive amount of a base such as sodium carbonate or potassiumcarbonate, in an aprotic polar solvent such as dimethylformamide (DMF),dimethylsulfoxide (DMSO), or hexamethylphosphoramide (HMPA) within atemperature range of 0° C. to a reflux temperature (preferably from roomtemperature to 80° C.) for 1-7 days. In the case in which neither R¹ norR² is a hydroxyl group, a compound (1a') of the present inventionwherein R³ is a Z--A-benzyl group may be by-produced, whereas in thecase in which R¹ and/or R² is a hydroxyl group, there may be by-produceda compound (1a") of the present invention wherein the hydrogen of thehydroxyl group has been substituted by a Z--A-benzyl group. For thisreason, in order to obtain a compound (1) of the present invention inwhich R¹ and/or R² is a hydroxyl group, the hydroxyl group of thecompound (2) is protected by use of an appropriate protective group,followed by removal of the protection (Method B). ##STR4## wherein R¹,R², A, Z, and X have the same meanings as described above, R⁴ representsa lower alkyl group which may have a substituent, R⁵ represents a loweralkyl group which may have a substituent, and m is an number between 1and 4 inclusive.

Alkylation of the compound (1a) transforms the compound (1a) into acompound (1c) of the present invention in which R³ is a substituted orunsubstituted lower alkyl group (R⁴) (Method C). Alternatively,haloalkylation transforms the compound (1a) into a compound (1d), whichmay further be piperazinylated to a compound (1d') of the presentinvention (Method D). ##STR5## wherein R¹, R³, A, Z, X, and m have thesame meanings as defined above, R⁶ represents a dialkylaminoalkyl group,R⁷ represents a lower alkyl group, and R⁸ represents an alkyl group.

The compound (1e) of the present invention in which R² is adialkylaminoalkoxy group is obtained through diaminoalkylation of thecompound (1b) in which R² is a hydroxyl group (Method E). Also, thecompound (1f') of the present invention in which R² is apiperazinylalkoxy group is obtained by haloalkylation of compound (1b)and by subsequent piperazinylation of the resultant compound (1f)(Method F). The compound (1g) of the present invention in which R² is analkylcarbonyloxy group is obtained through esterification of thehydroxyl group of compound (1b) (Method G).

Independently, the aforementioned compound (2), which serves as a rawmaterial of the compound (1) of the present invention may be formed asfollows. Briefly, a cyanoquinoline compound (4) is first formedaccording to a known method, e.g., a method described by Bhaduri, AmiyaPrasad et al.; J. Heterocyclic Chem., 23, 409-411, 1985, then thecyanoquinoline compound (4) is reacted with an azide compound such assodium azide, in an aprotic polar solvent such as DMF, DMSO, or HMPA, inthe presence of ammonium chloride, at a temperature between 0° C. and200° C. inclusive, preferably between room temperature to 120° C.inclusive, for several hours to one day. ##STR6## wherein R¹ and R² havethe same meanings as defined above.

Among several compounds of formula (3) which serve as another rawmaterials, the halogen compounds of formulas (3a) to (3c) may beprepared, for example, by the following processes.

The halogen compound (3a) may be commercially obtained, or may beprepared in accordance with a method described, for example, by Musser,John H. et al.; J. Med. Chem. 33(1), 240-245, 1990 or by Iemura, Ryuichiet al.; J. Heterocyclic. Chem. 24(1), 31-37, 1987.

The halogen compounds (3b) and (3c) may be prepared, for example, by thefollowing method. ##STR7## wherein R⁹ represents an alkyl group or aC1-C4 alkoxy C1-C4 alkyl group, and X represents a halogen atom.

When the halogen compound (3a) and hydroxybenzyl alcohol in anequivalent amount are allowed to react with each other in an aproticpolar solvent such as DMF, DMSO, or HMPA, in the presence of anexcessive amount of amount of a base such as sodium carbonate orpotassium carbonate, at a temperature between 0° C. and a refluxtemperature inclusive, preferably between room temperature to 60° C.inclusive, for one to 7 days, there is obtained a benzyl alcohol (5a).

Independently, a benzyl alcohol of formula (5b) may be prepared asfollows. The halogen (3a), together with an equivalent amount of PPh₃(Ph stands for phenyl), is first refluxed in an inert solvent such asbenzene, toluene, or xylene for 12-48 hours, to thereby synthesize acorresponding phosphonium salt. The phosphonium salt is allowed to reactwith an equimolar amount of t-BuOK (potassium tert-butoxide) in anabsolute THF under nitrogen or argon, to thereby prepare a Wittigreagent. To the Wittig reagent are added equimolar amounts of phthalicaldehyde, isophthalic aldehyde, and terephthalic aldehyde, and themixture is subjected to refluxing for 1 to 12 hours, to thereby obtainan aldehyde compound (6). The aldehyde compound (6) is then reacted withsodium borohalide in a protic polar solvent such as methanol or ethanolat a temperature between 0° C. and a reflux temperature inclusive,preferably at room temperature, for 1-24 hours, to thereby obtain thebenzyl alcohol (5b).

The thus-obtained benzyl alcohol (5a) or (5b) is allowed to react withan excessive amount of thionyl chloride in an inert solvent such as THF,Chloroform, or methylene chloride, at a temperature between 0° C. and areflux temperature inclusive, preferably at room temperature, for 1-24hours, to thereby obtain a halogen compound (3b) or (3c).

After completion of the above-described sequence of reactions, asuitable treatment of the obtained compound according to a customarymethod provides a target compound (1) of the present invention, whichmay further be purified by a customary purification means such asrecrystallization, column chromatography, etc., as desired. Ifnecessary, the compound may be converted into any one of theaforementioned salts.

The thus-obtained compounds (1) and their salts of the present inventionexhibit excellent anti-leukotriene activity and excellent antihistaminicactivity, as demonstrated by the below-described examples, and areuseful as remedies, including preventive drugs and therapeutic drugs,for asthma, allergic rhinitis, allergic conjunctivitis, atopicdermatitis, urticaria, psoriasis, rheumatism, inflammatory colitis,cerebral ischemia, and cerebral apoplexy.

The medicine of the present invention comprises as an active ingredientthe above-described compound (1), a salt thereof, or a hydrate of thecompound (1) or the salt. Examples of the manner of administration ofthe present medicine include oral administrations by way of tablets,capsules, granules, powders, and syrups and non-oral administrationssuch as intravenous injections, intramuscular injections, suppositories,inhalations, percutaneous absorptions, eye drops, and nasal drops. Inorder to prepare pharmaceutical preparations of a variety of forms, theaforementioned active ingredient may be used alone or in combinationwith a pharmaceutical vehicle, such as, for example, an excipient, abinder, a bulking agent, a disintegrant, a surfactant, a lubricant, adispersing agent, a buffering agent, a preservative, a flavoring agent,a perfume, a coating agent carrier, a diluent, etc.

The dosage of the medicine of the present invention varies in accordancewith the age, body weight, symptom, manner of administration, frequencyof the administration, etc. In general, in the case of adults, it ispreferred that the compound of the present invention be administered inan amount of 1-1,000 mg per day at a time or as divided in severaltimes, orally or non-orally.

EXAMPLES

The present invention will next be described by way of examples, whichshould not be construed as limiting the invention thereto.

Production Example 1 Synthesis of6-methoxy-3-tetrazolyl-1,2-dihydroquinolin-2-one sodium salt

3-Cyano-6-methoxy-1,2-dihydroquinolin-2-one (78.6 g, 393 mmol) wasdissolved in DMF (1 liter), and ammonium chloride (83.8 g, 1.57 mol) andsodium azide (102.2 g, 1.57 mol) were added to the resultant mixture.The mixture was stirred for 12 hours at a bath temperature of 120° C.The reaction mixture was concentrated under reduced pressure.Subsequently, an 2N sodium hydroxide aqueous solution (800 ml) was addedto the reaction mixture, and the mixture was heated. After removal ofthe insoluble matter by filtration, the filtrate was allowed to cool.The crystals that precipitated were collected, to thereby obtain thetitle compound as pale yellow needles (90.0 g, 339 mmol, 86.3%).

mp:>260° C.

¹ H-NMR (DMSO-d₆) δ (ppm): 11.9 (1H, br), 8.45 (1H, s), 7.34 (1H, d,J=1.5 Hz), 7.30 (1H, d, J=8.8 Hz), 7.15 (1H, dd, J=8.8, 1.5 Hz), 3.80(3H, s).

IR(KBr)cm⁻¹ : 3445, 1665, 1624, 1510, 1461, 1368, 1234, 1171, 1034, 638.

Production Example 2 Synthesis of6-tert-Butyl-3-tetrazolyl-1,2-dihydroquinolin-2-one

6-tert-Butyl-3-cyano-1,2-dihydroquinolin-2-one (1.74 g, 7.7 mmol) wasdissolved in DMF (20 ml), and ammonium chloride (1.65 g, 30.8 mol) andsodium azide (2.00 g, 30.8 mol) were added to the resultant mixture. Themixture was stirred at a bath temperature of 120° C. for 16 hours. Wateradded to the reaction mixture. After removal of the precipitates byfiltration, the reaction mixture was recrystallized from DMF-methanol.The crystals that precipitated were collected, to thereby obtain thetitle compound as yellow powder (1.08 g, 4.0 mmol, 52%).

mp: 280-286° C. (d.)

¹ H-NMR (CDCl₃) δ (ppm): 8.96 (1H, s), 7.95 (1H, d, J=2.2 Hz), 7.75 (1H,dd, J=8.5, 2.2 Hz), 7.39 (1H, d, J=8.5 Hz), 1.34 (9H, s).

IR(KBr)cm⁻¹ : 2964, 1667, 1625, 1535, 1473, 1365, 1261, 1156, 1036, 626

Production Examples 3 through 7

In a manner similar to that of Production Examples 1 and 2, thefollowing compounds were obtained.

                  TABLE 1                                                         ______________________________________                                        Ex. Compound             Property  m.p.                                       ______________________________________                                        3   7-Hydroxy-3-tetrazolyl-1,2-                                                                        Brown     >280° C.                               dihydroquinolin-2-one powder                                                 4 8-Hydroxy-3-tetrazolyl-1,2- Brown >280° C.                            dihydroquinolin-2-one powder                                                 5 Sodium 6-methoxymethoxy-3- Pale yellow >270° C.                       tetrazolyl-1,2-dihydroquinolin-2-one scales                                  6 3-Tetrazolyl-1,2-dihydroquinolin-2- Pale yellow >280° C.                                                one powder                                 7 5-Ethoxy-8-methyl-3-tetrazolyl-1,2- Yellow 278˜280° C.                                            dihydroquinolin-2-one powder             ______________________________________                                                                           (d.)                                   

Production Example 8 Synthesis of 3-(2-quinolylmethoxy)benzyl chloride

To a solution of 3-(2-quinolylmethoxy)benzyl alcohol 3.58 g, 13.5 mmol)in CHCl₃ (100 ml) was added SOCl₂ (2 ml). The mixture was stirred atroom temperature for 24 hours. A small amount of methanol was added tothe reaction mixture, and the solvent thereof was removed under reducedpressure, to thereby obtain the title compound as white powder.

Production Example 9 Synthesis of 2-(2-quinazolylmethoxy)benzyl alcohol

To a solution of 2-Chloromethylquinazoline (5.00 g, 28 mmol) in DMF (50ml) were added potassium carbonate (4.26 g, 31 mmol) andtetra-n-butylammoniumbromide (903 mg, 2.8 mmol). 3-Hydroxybenzylalcohol(3.48 g, 28 mmol) was added to the resultant mixture, and the mixturewas stirred at room temperature for five days. Subsequently, thereaction mixture was concentrated under reduced pressure. Chloroform andwater were added to the resultant mixture, and the organic phase wasextracted from the mixture. The organic phase was dried over sodiumsulfate anhydrate, concentrated under reduced pressure, andrecrystallized from a chloroform-n-hexane mixture, to thereby obtain thetitle compound as pale yellow powder (6.94 g, yield: 93.1%).

mp: 92-96° C.

¹ H-NMR(CDCl₃) δ (ppm): 9.43(1H, s, --C₈ H₅ N₂ --), 8.07 (1H, d, J=9.0Hz, --C₈ H₅ N₂ --), 7.95 (1H, d, J=7.5 Hz, --C₈ H₅ N₂ --), 7.93 (1H, d,J=9.0 Hz, --C₈ H₅ N₂ --), 7.67 (1H, dd, J=7.5, 7.5 Hz, --C₈ H₅ N₂ --),7.25 (1H, dd, J=7.8, 7.8 Hz, --C₆ H₄ --), 7.11 (1H, s, --C₆ H₄ --), 6.99(1H, d, J=7.8 Hz, --C₆ H₄ --), 6.96 (1H, d, J=7.8 Hz, --C₅ H₄ --), 5.46(2H, s, C₈ H₅ N₂ --CH₂ --), 4.65 (2H, s, --C₆ H₄ --CH₂ --OH).

IR(KBr)cm⁻¹ : 3328, 1621, 1613, 1582, 1441, 1378, 1292, 1077, 752.

Production Example 10 Synthesis of3-(N-methylbenzimidazol-2-ylmethoxy)benzyl alcohol

In a manner similar to that of Production Example 9, the title compoundwas obtained as pale yellow needles by use of2-chloromethyl-N-methylbenzimidazole (yield: 58.4%).

mp: 183-185° C.

¹ H-NMR (CDCl₃) δ (ppm): 7.69 (1H, m, C₈ H₇ N₂ --), 7.16-7.32 (4H, m,Ar--H), 7.02 (1H, s, --C₆ H₄ --), 6.88-6.94 (2H, m, --C₆ H₄ --), 5.29(2H, s, C₈ H₇ N₂ --CH₂ --), 4.61 (2H, s, --C₆ H₄ --CH₂ --OH), 3.81 (3H,s, N--CH₃).

IR(KBr)cm⁻¹ : 2850, 1594, 1482, 1441, 1366, 1259, 1227, 1048, 1029, 750.

Production Example 11 Synthesis of4-(2-N-methylbenzimidazol-2-ylmethoxy)benzyl alcohol

In a manner similar to that of Production Example 9, the title compound(yield: 46.7%) was obtained as pale yellow prisms by use of2-Chloromethyl-N-methylbenzimidazole and 4-Hydroxybenzyl alcohol.

mp: 176-180° C.

¹ H-NMR (CDCl₃) δ (ppm): 7.78 (1H, m, C₈ H₇ N₂ --), 7.23-7.38 (3H, m, C₈H₇ N₂ --), 7.30 (2H, d, J=8.6 Hz, --C₆ H₄ --), 7.04 (2H, d, J=8.6 Hz,--C₆ H₄ --), 5.34 (2H, s, C₈ H₇ N₂ --CH₂ --), 4.62 (2H, s, --C₆ H₄ --CH₂--OH), 3.88 (3H, s, N--CH₃).

IR(KBr)cm⁻¹ : 3174, 2846, 1607, 1585, 1507, 1484, 1240, 1047, 1030, 734.

Production Example 12 Synthesis of3-[N-(2-ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl alcohol

In a manner similar to that of Production Example 9, the title compound(yield: 90.3%) was obtained as colorless needles by use of2-Chloromethyl-N-(2-ethoxyethyl)benzimidazole.

mp: 105-107° C.

¹ H-NMR (CDCl₃) δ (ppm): 7.71 (1H, m, Ar--H), 7.41 (1H, m, Ar--H),7.23-7.34 (3H, m, Ar--H), 7.11 (1H, s, --C₆ H₄ --), 6.96-7.62 (2H, m,--C₆ H₄ --), 5.43 (2H, s, C₁₁ H₁₃ N₂ O--CH₂ O--), 4.68 (2H, d, J=5.6 Hz,--C₆ H₄ --CH₂ OH), 4.48 (2H, t, J=5.4 Hz, --CH₂ --CH₂ OCH₂ CH₃), 3.74(2H, t, J=5.4 Hz, --CH₂ CH₂ OCH₂ CH₃), 3.39 (2H, q, J=6.8 Hz, CH₂ CH₂OCH₂ CH₃), 2.24 (1H, br, --C₆ H₄ --CH₂ OH), 1.10 (3H, t, J=6.8 Hz, CH₂CH₂ OCH₂ CH₃).

IR(KBr)cm⁻¹ : 2875, 1594, 1471, 1445, 1426, 1369, 1258, 1154, 1050,1035, 761.

Production Example 13 Synthesis of4-[N-(2-ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl alcohol

In a manner similar to that of Production Example 9, the title compound(yield: 83.4%) was obtained as pale yellow prisms by use of2-chloromethyl-N-(2-ethoxyethyl)benzimidazole and 4-Hydroxybenzylalcohol.

mp: 90-92° C.

¹ H-NMR (CDCl₃) δ (ppm): 7.78 (1H, m, Ar--H), 7.41 (1H, m, Ar--H),7.25-7.34 (4H, m, Ar--H), 7.08 (2H, d, J=8.8 Hz, --C₆ H₄ --), 5.44 (2H,s, C₁₁ H₁₃ N₂ O--CH₂ O--), 4.62 (2H, d, J=5.7 Hz,--C₆ H₄ --CH₂ --OH),4.49 (2H, t, J=5.6 Hz, --CH₂ --CH₂ OCH₂ CH₃), 3.75 (2H, t, J=5.6 Hz,--CH₂ CH₂ OCH₂ CH₃), 3.39 (2H, q, J=7.1 Hz, CH₂ CH₂ OCH₂ CH₃), 1.66 (1H,t, J=5.7 Hz, --C₆ H₄ --CH₂ OH), 1.10 (3H, t, J=7.1 Hz, CH₂ CH₂ OCH₂CH₃).

IR (KBr) cm⁻¹ : 3180, 2858, 1609, 1587, 1509, 1472, 1417, 1237, 1117,1036, 747.

Production Example 14 Synthesis of 3-[2-(2-quinolyl)ethenyl]benzylalcohol

3-[2-(2-quinolyl)ethenyl]benzyl aldehyde (25.92 g, 0.1 mol) wasdissolved in methanol (300 ml). Sodium borohydride (7.57 g, 0.2 mol) wasadded to the resultant mixture, and the mixture was stirred at roomtemperature for one hour. The solvent of the reaction mixture wasremoved under reduced pressure. Water was added to the obtained residue,and the organic phase was extracted from the solution with ethylacetate. The organic phase was dried over magnesium sulfate anhydrate,and recrystallized from ethyl acetate, to thereby obtain the titlecompound as pale yellow powder (21.42 g, 82.0 mmol, 82.0%).

Production Examples 15 Through 22

In a manner similar to that of Production Example 8, the followingcompounds were obtained.

                  TABLE 2                                                         ______________________________________                                        Ex.     Compound             Property                                         ______________________________________                                        15      4-(2-Quinolylmethoxy)benzyl                                                                        White                                               chloride powder                                                              16 3-(2-Quinazolylmethoxy)benzyl White                                         chloride powder                                                              17 4-(2-Quinazolylmethoxy)benzyl White                                         chloride powder                                                              18 3-(2-N-Methylbenzimidazol-2- White                                          ylmethoxy)benzyl chloride powder                                             19 4-(2-N-Methylbenzimidazol-2- White                                          ylmethoxy)benzyl chloride powder                                             20 3-[N-(2-Ethoxyethyl)benzimidazol- Pale yellow                               2-ylmethoxy]benzyl chloride oily                                               material                                                                    21 4-[N-(2-Ethoxyethyl)benzimidazol- Pale yellow                               2-ylmethoxy]benzyl chloride oily                                               material                                                                    22 3-[2-(2-Quinolyl)ethenyl]benzyl White                                       chloride powder                                                            ______________________________________                                    

Examples 1 and 2 Synthesis of6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-oneand6-methoxy-3-{1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

To 6-methoxy-3-tetrazolyl-1,2-dihydroquinolin-2-one sodium salt (36.7 g,138 mmol), sodium carbonate (14.7 g, 138 mmol), andtetra-n-butylammoniumbromide (22.3 g, 66.1 mmol), was added DMF (2liters). (2-Quinolylmethoxy)benzyl chloride (58.7 g) was added to theresultant mixture, and the mixture was stirred for 15 hours at a bathtemperature of 80° C. Subsequently, the solvent of the reaction mixturewas removed under reduced pressure. To the obtained residue was added an2N sodium hydroxide aqueous solution (1 liter). The organic phase wasextracted from the solution with a mixture of chloroform-methanol (5:1).The organic phase was dried over sodium sulfate anhydrate,recrystallized from ethyl acetate, subjected to silica gel columnchromatography (chloroform-methanol (5:1)), and concentrated underreduced pressure. The obtained residue was recrystallized from achloroform-methanol-ether mixture, to thereby obtain crude6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one asfirst-deposited crystals, and crude6-methoxy-3-{1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one assecond-deposited crystals.

The first-deposited crystals were further purified throughrecrystallization (with DMF-ether), to thereby obtain6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(24.0 g, yield: 35.4%) as yellow powder.

mp: 213-214° C. (d.)

¹ H-NMR (DMSO-d₆) δ (ppm): 12.01 (1H, br), 8.56 (1H, s), 8.39 (1H, d,J=8.3 Hz), 8.00 (1H, d, J=7.8 Hz), 8.03-7.94 (2H, m), 7.76 (1H, ddd,J=8.3, 6.8, 1.5 Hz), 7.67 (1H, d, J=8.3 Hz), 7.59 (1H, m), 7.41 (1H, d,J=2.5 Hz), 7.35 (1H, dd, J=7.8, 7.8 Hz), 7.31 (1H, d, J=8.8 Hz), 7.25(1H, dd, J=8.8, 2.5 Hz), 7.15-7.06 (2H, m), 6.98 (1H, d, J=7.8 Hz), 5.99(2H, s), 5.37 (2H, s), 3.80 (3H, s).

IR (KBr) cm⁻¹ : 3432, 1676, 1629, 1587, 1497, 1378, 1285, 1239, 1165,1030, 829, 598.

Also, the second-deposited crystals were further purified throughrecrystallization (with DMF-ether), to thereby obtain6-methoxy-3-{1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(12.1 g, yield: 19.0%) as pale yellow powder.

mp: 215-217° C. (d.)

¹ H-NMR (DMSO-d₆) δ (ppm): 12.39 (1H, br), 8.35 (1H, d, J=8.8 Hz), 8.31(1H, s), 8.00 (1H, d, J=7.8 Hz), 7.98 (1H, d, J=7.3 Hz), 7.78 (1H, ddd,J=8.3, 6.8, 1.5 Hz), 7.62 (1H, dd, J=7.8, 7.3 Hz), 7.55 (1H, d, J=8.3Hz), 7.38 (1H, d, J=8.8 Hz), 7.34-7.27 (2H, m), 7.20 (1H, m), 6.97-6.90(2H, m), 6.77 (1H, d, J=7.8 Hz), 5.73 (2H, s), 5.23 (2H, s), 3.78 (3H,s).

IR (KBr) cm⁻¹ : 3434, 1665, 1625, 1498, 1453, 1380, 1264, 1244, 1171,1034, 827.

Examples 3 Through 34

In a manner similar to that of Examples 1 and 2, the compounds shown inTables 3 and 4 below were obtained.

                  TABLE 3                                                         ______________________________________                                        Ex. Compound                   m.p.                                           ______________________________________                                        3   3-{1-{3-[N-(2-Ethoxyethyl)benzimidazol-2-                                                                200˜202° C.                          ylmethoxy]benzyl}tetrazolyl}-6-hydroxyquinolin-2- (d.)                        one                                                                          4 3-{1-{4-[N-(2-Ethoxyethyl)benzimidazol-2- 240˜242° C.                                         ylmethoxy]benzyl}tetrazolyl}-6-hydroxyqui                                   nolin-2- (d.)                                     one                                                                          5 3-{2-{4-[N-(2-Ethoxyethyl)benzimidazol-2- 245˜248° C.                                         ylmethoxy]benzyl}tetrazolyl}-6-hydroxyqui                                   nolin-2- (d.)                                     one                                                                          6 3-{2-{4-[N-(2-Ethoxyethyl)benzimidazol-2- 200˜202° C.                                         ylmethoxy]benzyl}tetrazolyl}-6-methoxyqui                                   nolin-2-                                          one                                                                          7 3-{1-{4-[N-(2-Ethoxyethyl)benzimidazol-2- 234˜236° C.                                         ylmethoxy]benzyl}tetrazolyl}-6-methoxyqui                                   nolin-2- (d.)                                     one                                                                          8 3-{2-[3-(N-Methylbenzimidazol-2- 262˜265° C.                    ylmethoxy)benzyl]tetrazolyl}quinolin-2-one (d.)                              9 3-{1-[3-(N-Methylbenzimidazol-2- 234˜236° C.                    ylmethoxy)benzyl]tetrazolyl}quinolin-2-one (d.)                              10 6-Methoxy-3-{2-[3-(2-quinazolylmethoxy)- 186˜189° C.                                         benzyl]tetrazolyl}quinolin-2-one                                             11 6-Methoxy-3-{2-[4-(2-quinazolylmethoxy)                                   - 197˜199° C.                        benzyl]tetrazolyl}quinolin-2-one (d.)                                        12 6-Methoxy-3-{1-[4-(2-quinazolylmethoxy)- 197˜199° C.                                         benzyl]tetrazolyl}quinolin-2-one (d.)                                        13 6-Methoxy-3-{2-{3-[2-(2-quinolyl)etheny                                   l]- 241˜244° C.                      benzyl}tetrazolyl}quinolin-2-one (d.)                                        14 6-Methoxy-3-{1-{3-[2-(2-quinolyl)ethenyl]- 250˜252° C.                                       benzyl}tetrazolyl}quinolin-2-one (d.)                                        15 5-Ethoxy-8-methyl-3-{2-[3-(2-quinolylme                                   thoxy)- 221˜223° C.                  benzyl]tetrazolyl}quinolin-2-one                                             16 5-Ethoxy-8-methyl-3-{2-[4-(2-quinolylmethoxy)- 150˜154°                                    C.                                                benzyl]tetrazolyl}quinolin-2-one (d.)                                        17 6-tert-Butyl-3-{2-[3-(2-quinolylmethoxy)- 102˜105° C.                                        benzyl]tetrazolyl}quinolin-2-one                                             18 6-tert-Butyl-3-{1-[3-(2-quinolylmethoxy                                   )- 105˜107° C.                       benzyl]tetrazolyl}quinolin-2-one                                           ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Ex. Compound                   m.p.                                           ______________________________________                                        19  6-tert-Butyl-3-{1-[4-(2-quinolylmethoxy)-                                                                216˜219° C.                          benzyl]tetrazolyl}quinolin-2-one                                             20 7-Hydroxy-3-{1-[3-(2-quinolylmethoxy)benzyl]- 262˜264°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               21 8-Hydroxy-3-{1-[3-(2-quinolylmethoxy)benzyl]- 262˜264°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               22 6-Hydroxy-3-{2-[4-(2-quinolylmethoxy)benzyl]- 231˜234°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               23 6-Hydroxy-3-{1-[4-(2-quinolylmethoxy)benzyl]- 250˜252°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               24 6-Methoxy-3-{2-[4-(2-quinolylmethoxy)benzyl]- 206˜210°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               25 6-Methoxy-3-{1-[4-(2-quinolylmethoxy)benzyl]- 206˜209°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               26 3-{2-[3-(2-Quinolylmethoxy)benzyl]- 226˜229° C.                                              tetrazolyl}quinolin-2-one (d.)                 27 3-{1-[3-(2-Quinolylmethoxy)benzyl]- 238˜241° C.                                              tetrazolyl}quinolin-2-one (d.)                 28 6-Hydroxy-3-{2-[3-(2-quinolylmethoxy)benzyl]- 260˜267°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               29 6-Hydroxy-3-{1-[3-(2-quinolylmethoxy)benzyl]- 272˜275°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               30 6-[3-(2-Quinolylmethoxy)benzyl]oxy-3-{2-[3-(2- 195˜199°                                    C.                                                quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (d.)                        31 1-[3-(2-Quinolylmethoxy)benzyl]-3-{2-[3-(2- 114˜116° C.        quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one                             32 6-Hydroxy-1-[3-(2-quinolylmethoxy)benzyl]-3-{2- 175˜178°                                    C.                                               [3-(2-quinolylmethoxy)benzyl]tetrazolyl} (d.)                                 quinolin-2-one                                                               33 6-tert-Butyl-1-[3-(2-quinolylmethoxy)benzyl]-3- 96˜99°                                     C.                                                {1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}                                   quinolin-2-one                                                               34 6-Methoxy-1-[4-(N-methylbenzimidazole-2- 217˜219° C.                                         ylmethoxy)benzyl]-3-{2-[4-N-methylbenzimi                                   dazol-                                            2-ylmethoxy)benzyl]tetrazolyl}quinolin-2-one                               ______________________________________                                    

Examples 35 and 36 Synthesis of6-methoxymethoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-oneand6-methoxymethoxy-3-{1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

In a manner similar t that of Examples 1 and 2, the title compounds wereobtained.

The data of6-methoxymethoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-oneare as follows:

mp: 197-200° C. (d.)

¹ H-NMR (CDCl₃) δ (ppm): 11.24 (1H, br), 8.63 (1H, s), 8.18 (1H, d,J=8.3 Hz), 8.09 (1H, d, J=8.5 Hz), 7.72 (1H, ddd, J=8.5, 7.1, 1.5 Hz),7.64 (1H, d, J=8.5 Hz), 7.52 (1H, ddd, J=8.1, 6.8, 1.2 Hz), 7.35-7.24(4H, m), 7.13 (1H, m), 7.10-6.99 (2H, m), 5.87 (2H, s), 5.39 (2H, s),5.20 (2H, s), 3.50 (3H, s).

IR (KBr) cm⁻¹ : 1667, 1623, 1588, 1510, 1493, 1443, 1428, 1289, 1230,1155, 1074, 996, 825, 529.

The data of6-methoxymethoxy-3-{1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-oneare as follows:

mp: 202-206° C. (d.)

¹ H-NMR (CDCl₃) δ (ppm): 11.60 (1H, br), 8.13 (1H, s), 8.12 (1H, d,J=8.8 Hz), 8.05 (1H, d, J=8.4 Hz), 7.82 (1H, d, J=7.0 Hz), 7.73 (1H, dd,J=8.1, 7.0 Hz), 7.59-7.49 (2H, m), 7.34-7.19 (3H, m), 7.16 (1H, dd,J=8.7, 8.7 Hz), 5.86 (2H, s), 5.37 (2H, s), 5.21 (2H, s), 3.47 (3H, s).

IR (KBr) cm⁻¹ : 1664, 1623, 1600, 1497, 1291, 1266, 1158, 1001, 983,825, 781, 750.

Example 37

(Alternative Synthesis Method for Obtaining the Compound of Example 28)

Synthesis of6-hydroxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

6-methoxymethoxy-3-{2-[3-(2-quinolylmethoxy)-benzyl]tetrazolyl}quinolin-2-one(444 mg, 0.85 mmol) was dissolved in a mixture (100 ml) ofchloroform-methanol (10:1). A solution (5 ml) of hydrochloric acid (4N)in ethyl acetate was added to the resultant mixture, and the mixture wasstirred at room temperature for 17 hours. Water (400 ml) was addedthereto, and a saturated aqueous solution of sodium hydrogencarbonatewas added dropwise so as to neutralize the aqueous phase, followed byextraction with a mixture of chloroform-methanol (10:1). The organicphase was dried over magnesium sulfate anhydrate, and the solvent wasremoved under reduced pressure. The residue was recrystallized from achloroform-methanol-diethylether mixture, to thereby obtain the titlecompound as yellow leaf crystals (353 mg, 0.74 mmol, 87.2%).

mp: 260-267° C. (d.)

¹ H-NMR (CDCl₃ -CD₃ OD) δ (ppm): 8.53 (1H, s), 8.35 (1H, d, J=8.6 Hz),8.06 (1H, d, J=8.3 Hz), 7.89 (1H, d, J=8.3 Hz), 7.78 (1H, ddd, J=8.6,7.1, 1.5 Hz), 7.72 (1H, d, J=8.6 Hz), 7.60 (1H, m), 7.33 (1H, dd, J=8.8,8.1 Hz), 7.27 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=8.8, 2.8 Hz), 7.15-7.02(4H, m), 5.88 (2H, s), 5.39 (2H, s).

IR (KBr) cm⁻¹ : 1661, 1614, 1508, 1429, 1287, 1229, 1160, 1029, 826,781.

Example 38 Synthesis of6-methoxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

To a mixture of6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(1.61 g, 3.30 mmol) and potassium carbonate (684 mg, 4.95 mmol), wasadded DMF (30 ml). Methyl iodinate (562 mg, 3.96 mmol) was addeddropwise to the resultant mixture, and thereafter stirred for four hoursat a bath temperature of 80° C. The solvent of the reaction mixture wasremoved under reduced pressure. Water was added to the mixture, and theorganic phase was extracted therefrom with a mixture ofchloroform-methanol (10:1). The organic phase was dried over sodiumsulfate anhydrate, subjected to silica gel column chromatography (withchloroform-methanol (50:1)), and concentrated under reduced pressure.The resultant residue was recrystallized from a chloroform-n-hexan-ethermixture, to thereby obtain the title compound (1.35 g, 2.68 mmol, 81.1%)as pale yellow powder.

mp: 125-127°

¹ H-NMR (CDCl₃) δ (ppm): 8.57 (1H, s), 8.19 (1H, d, J=8.6 Hz), 8.07 (1H,d, J=8.5 Hz), 7.81 (1H, d, J=8.3 Hz), 7.72 (1H, ddd, J=8.3, 6.8, 1.5Hz), 7.64 (1H, d, J=8.6 Hz), 7.53 (1H, dd, J=8.3, 7.8 Hz), 7.36 (1H, d,J=9.0 Hz), 7.32-7.24 (2H, m), 7.13-7.09 (2H, m), 7.04 (1H, d, J=7.6 Hz),6.99 (1H, dd, J=7.6, 2.2 Hz), 5.85 (2H, s), 5.36 (2H, s), 3.89 (3H, s),3.81 (3H, s).

IR (KBr) cm⁻¹ : 3442, 1664, 1589, 1577, 1442, 1237, 1160, 1066, 1031,928, 786, 768.

Examples 39 Through 43

In a manner similar to that of Example 38, the compounds shown in Table5 below were obtained.

                  TABLE 5                                                         ______________________________________                                        Ex.  Compound                  m.p.                                           ______________________________________                                        39   1-Dimethylaminoethyl-6-hydroxy-3-{2-[3-(2-                                                              179˜181° C.                          quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (d.)                        40 1-Dimethylaminoethyl-6-hydroxy-3-{1-[3-(2- 153˜155° C.                                       quinolylmethoxy)benzyl]tetrazolyl}quinoli                                   n-2-one                                          41 1-Dimethylaminoethyl-6-methoxy-3-{2-[3-(2- 154˜158° C.                                       quinolylmethoxy)benzyl]tetrazolyl}quinoli                                   n-2-one                                          42 1-Dimethylaminopropyl-6-hydroxy-3-{2-[3-(2- 169˜172° C.        quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (d.)                        43 1-Dimethylaminoethyl-6-hydroxy-3-{2-[3-(2- 148˜152° C.                                       quinolylethenyl)benzyl]tetrazolyl}quinoli                                   n-2-one (d.)                                   ______________________________________                                    

Example 44 Synthesis of1-(3-chloropropyl)-6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

A mixture of6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(1.00 g, 2.04 mmol), potassium, carbonate (564 mg, 4.08 mmol),1-bromo-3-chloropropane (962 mg, 6.12 mmol), and DMF (100 ml) wasstirred for four hours at a bath temperature of 60° C. The solvent ofthe reaction mixture was removed under reduced pressure. Water was thenadded to the mixture, and the mixture was extracted withchloroform-methanol (10:1). The thus-obtained organic phase was driedover magnesium sulfate anhydrate, and the solvent was removed underreduced pressure. The organic phase was then subjected to silica gelcolumn chromatography (developer: chloroform-methanol (100:1)),purified, and crystallized from a chloroform-diethylether mixture, tothereby obtain the title compound (546 mg, 0.963 mmol, 47.2%) as paleyellow powder.

mp: 150-152° C.

¹ H-NMR (CDCl₃) δ (ppm): 8.60 (1H, s), 8.18 (1H, d, J=8.5 Hz), 8.07 (1H,d, J=8.3 Hz), 7.81 (1H, d, J=9.0 Hz), 7.72 (1H, ddd, J=8.3, 7.8, 1.5Hz), 7.64 (1H, d, J=8.3 Hz), 7.53 (1H, dd, J=8.1, 6.8 Hz), 7.46 (1H, d,J=9.3 Hz), 7.33-7.24 (2H, m), 7.15-7.08 (2H, m), 7.06-6.96 (2H, m), 5.85(2H, s), 5.36 (2H, s), 4.53 (2H, t, J=7.8 Hz), 3.89 (3H, s), 3.73 (2H,t, J=6.3 Hz), 2.29 (2H, m).

IR (KBr) cm⁻¹ : 1660, 1590, 1573, 1508, 1445, 1428, 1267, 1159, 829,767.

Further, the by-product was crystallized from a chloroform-diethylethermixture, to thereby obtain2-chloropropoxy-6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinoline(173 mg, 0.305 mmol, 15.0%) as white powder.

Example 45 Synthesis of1-{3-[4-(2-quinolylmethyl)-1-piperazinyl]propyl}-6-methoxy-3-(2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl)quinolin-2-onedihydrochloride

A mixture of1-(3-chloropropyl)-6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(179 mg, 0.316 mmol) and N-(2-quinolylmethyl)piperazine (287 mg, 1.26mmol) was stirred under an argon flow at 120° C. for 2.5 hours. Themixture was allowed to cool, subjected to silica gel columnchromatography (developer: chloroform-methanol (40:1)), and purified.Fractions including the target compound were collected, and concentratedunder reduced pressure, to thereby obtain the free base of the titlecompound (219 mg, 0.289 mmol) as yellow oily matter. The thus-obtainedfree base of the title compound was dissolved in methanol (50 ml), and asolution of hydrochloric acid (4N) in ethyl acetate (144 μl, 0.576 mmol)was added to the resultant mixture. The mixture was crystallized from amethanol-diethylether mixture, to thereby obtain the title compound (184mg, 0.22 mmol, 70.1%) as yellow powder.

mp: 182-186°

¹ H-NMR (CDCl₃ -CD₃ OD) δ (ppm): 8.73 (1H, d, J=8.6 Hz), 8.66 (1H, d,J=8.1 Hz), 8.60 (1H, s), 8.53 (1H, d, J=8.1 Hz), 8.05-7.79 (6H, m), 7.70(1H, dd, J=7.8, 7.3 Hz), 7.59 (1H, d, J=9.3 Hz), 7.40-7.30 (2H, m),7.22-7.15 (2H, m), 7.10-7.04 (2H, m), 5.88 (2H, s), 5.55 (2H, s), 4.53(2H, t, J=6.3 Hz), 4.34 (2H, s), 3.91 (3H, s), 3.54 (4H, br), 3.37 (2H,m), 3.22 (4H, br), 2.37 (2H, m).

IR (KBr) cm⁻¹ : 1652, 1625, 1576, 1509, 1455, 1240, 1028, 772, 475.

Examples 46 Through 49

In a manner similar to that of Example 45, the compounds shown in Table6 below were obtained.

                  TABLE 6                                                         ______________________________________                                        Ex. Compound                   m.p.                                           ______________________________________                                        46  6-Methoxy-1-[3-(4-methylpiperazinyl)propyl]-3-{2-                                                        191˜195° C.                          [3-(2-quinolylmethoxy)benzyl]tetrazolyl} (d.)                                 quinolin-2-one                                                               47 6-Methoxy-1-{4-[4-(2-quinolylmethyl)- 179˜181° C.                                            piperazinyl]butyl}-3-{2-[3-(2- (d.)                                           quinolylmethoxy)benzyl]tetrazolyl}                                            quinolin-2-one dimalate                        48 6-Methoxy-1-{3-[4-(2-pyridylmethyl)- 161˜164° C.                                             piperazinyl]propyl}-3-{2-[3-(2- (d.)                                          quinolylmethoxy)benzyl]tetrazolyl}                                            quinolin-2-one dihydrochloride                 49 6-Methoxy-3-{2-[3-(2-quinolylethenyl)benzyl]- 156˜158°                                     C.                                                tetrazolyl}-1-{3-[4-(2-quinolylmethyl)- (d.)                                  piperazinyl]propyl}quinolin-2-one dimalate                                 ______________________________________                                    

Example 50 Synthesis of6-dimethylaminoethoxy-1-dimethylaminoethyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-onedioxalate

To a mixture of6-dimethylaminoethyl-3-1-hydroxy-{1-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(700 mg, 1.28 mmol) and potassium carbonate (706 mg, 5.11 mmol), wasadded DMF (40 ml), and the resultant mixture was stirred.Dimethylaminoethylchloride (369 mg, 2.56 mmol) was then added to themixture, and the mixture was stirred for three days at a bathtemperature of 80° C.

The reaction mixture was concentrated under reduced pressure. Afteraddition of water, the reaction mixture was extracted with a mixture ofchloroform-methanol (10:1). The thus-obtained organic phase was driedover sodium sulfate anhydrate, and the solvent was removed under reducedpressure. The organic phase was then subjected to silica gel columnchromatography (with chloroform-ammonia-saturated-methanol (10:1)). Thesolvent of the fractions including the target compound was removed underreduced pressure, to thereby obtain the free base of the title compound(254 mg, 0.411 mmol, 32.1%) as brown oily matter.

¹ H-NMR (CDCl₃) δ (ppm): 8.57 (1H, s), 8.18 (1H, d, J=8.5 Hz), 8.06 (1H,d, J=8.3 Hz), 7.81 (1H, d, J=8.1 Hz), 7.73 (1H, ddd, J=8.5, 6.8, 1.5Hz), 7.64 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.2, 6.8 Hz), 7.40 (1H, d,J=9.3 Hz), 7.34-7.23 (2H, m), 7.14 (1H, d, J=2.7 Hz), 7.10 (1H, s),7.05-6.95 (2H, m), 5.86 (2H, s), 5.36 (2H, s), 4.50 (2H, t, J=8.1 Hz),4.13 (2H, t, J=5.6 Hz), 2.77 (2H, t, J=5.6 Hz), 2.67 (2H, t, J=8.1Hz),2.40 (6H, s), 2.36 (6H, s).

The thus-obtained free base of the title compound was dissolved inmethanol, and oxalic acid (148 mg, 0.422 mmol) was added to theresultant mixture. Subsequently, the mixture was recrystallized from anacetone-ether mixture, to thereby obtain the dioxalate (211 mg, 0.270mmol, 21.1%) of the title compound as brown powder.

mp: 172-176° C. (d.)

¹ H-NMR (CDCl₃) δ (ppm): 8.52 (1H, s), 8.24 (1H, d, J=8.1 Hz), 8.05 (1H,d, J=8.6 Hz), 7.84 (1H, d, J=7.6 Hz), 7.78-7.67 (2H, m), 7.66 (1H, d,J=8.5 Hz), 7.56 (1H, ddd, J=9.3, 8.1, 1.2 Hz), 7.47-7.38 (1H, m), 7.31(1H, dd, J=7.8, 8.1 Hz), 7.17 (1H, m), 7.12 (1H, m), 7.07-7.68 (2H, m),5.85 (2H, s), 5.35 (2H, s), 4.70 (2H, m), 4.40 (2H, m), 3.49 (2H, m),3.30 (2H, m), 2.95 (6H, s), 2.94 (6H, s).

IR (KBr) cm⁻¹ : 3419, 1652, 1599, 1509, 1448, 1312, 1281, 1239, 1161,1055, 831.

Example 51 Synthesis of6-(3-chloropropyl)oxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

To a mixture of6-hydroxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(600 mg, 1.22 mmol) and potassium carbonate (337 mg, 2.44 mmol), wasadded DMF (100 ml), and the resultant mixture was stirred.1-Bromo-3-chloropropane (578 mg, 3.64 mmol) was then added thereto,followed by stirring at a bath temperature of 60° C. for four hours. Thereaction mixture was concentrated under reduced pressure, and water wasadded thereto, followed by extraction with a mixture ofchloroform-methanol (10:1). The residue was dried over sodium sulfateanhydrate, and the solvent was removed under reduced pressure, tothereby obtain the title compound (638 mg) in a crude form as yellowoily matter.

¹ H-NMR (CDCl₃) δ (ppm): 8.52 (1H, s), 8.17 (1H, d, J=8.6 Hz), 8.06 (1H,d, J=8.5 Hz), 7.80 (1H, d, J=8.1 Hz), 7.71 (1H, ddd, J=8.3, 7.1, 1.5Hz), 7.63 (1H, d, J=8.5 Hz), 7.51 (1H, dd, J=8.1, 6.8 Hz), 7.35-7.21(3H, m), 7.14-7.09 (2H, m), 7.04 (1H, d, J=7.6 Hz), 6.98 (1H, dd, J=8.3,2.4 Hz), 5.85 (2H, s), 5.35 (2H, s), 4.17 (2H, t, J=5.9 Hz), 3.84-3.73(5H, m), 2.27 (2H, t,J=6.1 Hz).

Example 52 Synthesis of1-methyl-6-[3-(4-metylpiperazinyl)propyl]oxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-onetrihydrochloride

A mixture of crude6-[3-chloropropyl]oxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one(180 mg, 0.317 mmol) and N-methylpiperazine (127 mg, 1.27 mmol) wasstirred under an argon flow at a bath temperature of 120° C. for 90minutes. The reaction mixture was concentrated under reduced pressure,and purified through silica gel chromatography (developer:chloroform-methanol (20:1)). Fractions containing the target compoundwere collected, and concentrated under reduced pressure, to therebyobtain the free base of the title compound (180 mg, 0.285 mmol) asyellow oily matter. The thus-obtained free base was dissolved inmethanol (2 ml), and a solution of hydrochloric acid (4N) in ethylacetate (285 μl, 1.14 mmol) was added thereto. The mixture wascrystallized from a methanol-diethylether mixture, to thereby obtain thetrihydrochloride; i.e., the title compound, as yellow needles (143 mg,0.203 mmol, 64.1%).

mp: 188-192° C. (d.)

¹ H-NMR (CDCl₃ -CD₃ OD) δ (ppm): 8.77 (1H, d, J=8.6 Hz), 8.54 (1H, s),8.46 (1H, d, J=8.8 Hz), 8.11 (1H, d, J=8.6 Hz), 8.08-7.98 (2H, m), 7.82(1H, dd, J=7.6, 7.3 Hz), 7.46-7.32 (2H, m), 7.30-7.05 (5H, m), 5.90 (2H,s), 5.69 (2H, s), 4.21 (2H, overlapped with solvent), 3.90-3.65 (11H,m), 3.51 (2H, m), 2.98 (3H, m), 2.41 (2H, br).

IR (KBr) cm⁻¹ : 1647, 1623, 1578, 1510, 1456, 1384, 1241, 1162, 1060,963.

Example 53 Synthesis of6-{3-[4-(2-quinolylmethyl)piperazinyl]propyl}oxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

In a manner similar to that of Example 52, the title compound wasobtained.

mp: 174-178° C. (d.)

¹ H-NMR(DMSO-d₃) δ (ppm): 8.62 (1H, d, J=8.3 Hz), 8.53 (1H, s), 8.48(1H, d, J=8.8 Hz), 8.21-7.97 (4H, m), 7.93-7.71 (5H, m), 7.66-7.50 (3H,m), 7.41-7.33 (2H, m), 7.16-7.07 (2H, m), 7.01 (1H, d, J=7.8 Hz), 6.00(2H, s), 5.42 (2H, s), 4.60 (2H, br), 4.17 (2H, t, J=6.1 Hz), 3.80-3.30(8H, overlapped with solvent), 3.69 (3H, s), 2.25 (2H, br).

IR (KBr) cm⁻¹ : 1647, 1600, 1578, 1509, 1449, 1430, 1239, 1159.

Example 54 Synthesis of6-butyryloxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one

6-Hydroxy-3-{2-[3-(quinolyln-2-ylmethoxy)benzyl]tetrazolyl}quinolin-2-one(250 mg, 0.522 mmol) was dissolved in pyridine (30 ml), and butyricanhydride (172 μl, 1.05 mmol) was added thereto, followed by stirring atroom temperature for 20 hours. A small amount of methanol was added tothe reaction mixture, and the solvent was then removed. The residue wasdissolved in a chloroform-methanol (10:1) mixture, followed bysequential washing with hydrochloric acid (2N), water, a saturatedaqueous solution of sodium hydrogencarbonate, and water. The organicphase was dried over magnesium sulfate anhydrate, and the solvent wasremoved under reduced pressure. The residue was purified through silicagel chromatography (developer: chloroform-methanol (10:1)), followed byrecrystallization with a chloroform-methanol-diethylether mixture, tothereby obtain the title compound as white powder (265 mg, 0.485 mmol,92.8%).

mp: 200-202° C. (d.)

¹ H-NMR (CDCl₃) δ (ppm): 11.1 (1H, br), 8.64 (1H, s), 8.16 (1H, d, J=8.8Hz), 8.05 (1H, d, J=8.1Hz), 7.79 (1H, d, J=8.1 Hz), 7.70 (1H, ddd,J=8.4, 7.0, 1.5 Hz), 7.62 (1H, d, J=8.4 Hz), 7.51 (1H, m), 7.42 (1H, d,J=2.2 Hz), 7.36-7.27 (3H, m), 7.14-6.98 (3H, m), 5.87(2H, s), 5.37(2H,s), 2.67(2H, t, J=7.3 Hz), 1.80(2H, tq, J=7.3, 7.3 Hz), 1.06 (3H, t,J=7.3 Hz).

IR (KBr) cm⁻¹ : 1755, 1675, 1586, 1497, 1453, 1226, 1156, 1030, 828,757.

Examples 55 Through 64

In a manner similar to that of Example 54, the following compounds wereobtained.

                  TABLE 7                                                         ______________________________________                                        Ex. Compound                   m.p.                                           ______________________________________                                        55  6-Butyryloxy-3-{1-[3-(2-quinolylmethoxy)benzyl]-                                                         189˜191° C.                          tetrazolyl}quinolin-2-one (d.)                                               56 6-Acetoxy-3-{2-[4-(2-quinolylmethoxy)benzyl]- 226˜228°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               57 6-Acetoxy-3-{1-[4-(2-quinolylmethoxy)benzyl]- 235˜238°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               58 6-Acetoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]- 222˜225°                                     C.                                                tetrazolyl}quinolin-2-one                                                    59 6-Acetoxy-3-{1-[3-(2-quinolylmethoxy)benzyl]- 218˜221°                                     C.                                                tetrazolyl}quinolin-2-one (d.)                                               60 6-Propionyloxy-3-{2-[3-(2-quinolylmethoxy)- 216˜218° C.        benzyl]tetrazolyl}quinolin-2-one (d.)                                        61 6-Propionyloxy-3-{1-[3-(2-quinolylmethoxy)- 201˜203° C.        benzyl]tetrazolyl}quinolin-2-one (d.)                                        62 6-Isobutyryloxy-3-{2-[3-(2- 195˜197° C.                        quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (d.)                        63 6-Isobutyryloxy-3-{1-[3-(2-quinolylmethoxy)- 196˜199°                                      C.                                                benzyl]tetrazolyl}quinolin-2-one (d.)                                        64 6-Glycyloxy-3-{2-[3-(2-quinolylmethoxy)- 196˜200° C.                                         benzyl]tetrazolyl}quinolin-2-one             ______________________________________                                                                       (d.)                                       

Test Example 1

Antihistaminic Action and Antileukotriene Action (in vitro Test)

A guinea pig was subjected to ileectomy, and the ileum was cut tolengths of about 2 cm. Each piece of ileum was suspended in a Tyrode'sbuffer placed in a 20-ml organ bath. Isotonic contraction in response tohistamine or leukotriene D₄ as recorded by use of a recording apparatus.The Tyrode's buffer was aerated with a gas mixture (95% O₂ -5% CO₂)while the temperature of the buffer was maintained at 29° C.Antihstaminic activity was tested by adding 10⁻⁸ to 10⁻⁴ M histamine tothe organ bath and obtaining a dose-response curve. After washing with abuffer several times, a test compound was added to the organ bath.Thirty minutes later, another dose-response curve of histamine wasobtained. For the test of antileukotriene activity, there wereinvestigated effects exerted by addition of a 10⁻⁵ M test compound onthe contraction induced with 10⁻⁸ M LTD₄. In Table 8, antihistaminicaction is indicated by pA₂ or pD'₂, whereas antileukotriene action isindicated by IC₅₀.

                  TABLE 8                                                         ______________________________________                                        Example  Anti-histaminic action                                                                      Anti-LTD.sub.4 action IC.sub.50 (M)                    ______________________________________                                        1        5.53 pD'.sub.2                                                                              9.0 × 10.sup.-8                                    2 5.38 pA.sub.2 2.5 × 10.sup.-7                                         6 7.39 pA.sub.2 1.1 × 10.sup.-6                                         26 5.24 pD'.sub.2 1.79 × 10.sup.-7                                      38 5.52 pD'.sub.2 1.6 × 10.sup.-7                                       39 7.52 pA.sub.2 5.0 × 10.sup.-7                                        40 6.60 pA.sub.2 6.4 × 10.sup.-7                                        41 5.58 pD'.sub.2 5.9 × 10.sup.-7                                       42 7.26 pA.sub.2 8.4 × 10.sup.-7                                        43 6.76 pA.sub.2 3.6 × 10.sup.-6                                        45 7.66 pA.sub.2 6.4 × 10.sup.-7                                        47 7.70 pA.sub.2 2.1 × 10.sup.-6                                        48 6.94 pA.sub.2 5.0 × 10.sup.-7                                        52 6.04 pA.sub.2 1.3 × 10.sup.-6                                      ______________________________________                                    

Test Example 2

H₁ Receptor Binding Inhibitory Test

50 mM phosphate buffer (pH 7.5, 1 ml) containing 0.5 nM [³ H] mepyramine(activity: 22 Ci/mmol), guinea pig cerebral membrane protein, and a testcompound was incubated at 37° C. for 30 minutes. Reaction was stopped byaddition of ice-cold phosphate buffer, and immediately thereafter, thereaction mixture was filtered by use of a Wattman CF/C filter. Thefilter was washed twice, each time with 20 ml ice-cold buffer.Radioactivity of the residue was measured by use of a liquidscintillation counter. From the value as obtained when a test compoundwas not added and values as obtained when the test compound was added atdifferent concentrations, there was determined a dose-response curverepresenting suppression action of the test compound, from which a 50%inhibitory concentration (IC₅₀) was obtained. Based on the IC₅₀ valueand by use of the Cheng-Prusoff equation, a dissociation constant(K_(D)) was calculated (Table 9). In a saturation test, 10⁻⁴ MR(-)-dimetindene was used for the measurement of the amount ofnon-specific binding. From the saturation test, it was found that asingle type of receptor was involved, and the saturation amount ofbinding (Bmax) was 278±24 fmol/mg protein. Also, the dissociationconstant (K_(D)) of [³ H]mepyramine was 3.30±0.26×10⁻⁹ M, and the slopeas analyzed in accordance with Hill plots was 1.005. The figures inTable 9 represent dissociation constants K_(D) (M) or inhibition (%) ata high concentration (a: 100 μM, b: 10 μM).

Test Example 3

LTD₄ Receptor Binding Inhibitory Test

10 mM Piperazine N,N'-bis(2-ethane sulfonate) buffer (pH 7.5, 0.3 ml)containing 0.2 nM [³ H] leukotriene D₄, guinea pig lung protein, and atest compound was incubated at 22° C. for 30 minutes. Reaction wasstopped by addition of ice-cold Tris-HCl/NaCl (10 mM/100 mM, pH 7.5)buffer, and immediately thereafter, the reaction mixture was filtered byuse of a Wattman CF/C filter. The filter was washed twice, each timewith 20 ml ice-cold buffer. Radioactivity of the residue was measured byuse of a liquid scintillation counter. In a manner similar to thatapplied to the case of the H₁ receptor, IC₅₀ and the dissociationconstant (K_(D)) of the test compound were obtained (see Table 9). In asaturation test, 2 μM leukotriene D₄ was used for the measurement of theamount of non-specific binding. From the saturation test, it was foundthat there was involved a single type of receptor, and the saturationamount of binding (Bmax) was 988 fmol/mg protein. Also, the dissociationconstant (K_(D)) of [³ H]leukotriene D₄ was 2.16×10⁻¹⁰ M, and the slopeas analyzed in accordance with Hill plots was 0.99.

                  TABLE 9                                                         ______________________________________                                        Example   H.sub.1 Receptor K.sub.D (M)                                                               LTD.sub.4 Receptor K.sub.D (M)                         ______________________________________                                        1         2.96 × 10.sup.-6                                                                     1.14 × 10.sup.-7                                   6 3.29 × 10.sup.-6 8.11 × 10.sup.-6                               8 9.38 × 10.sup.-6 1.43 × 10.sup.-7                               9 1.37 × 10.sup.-5 3.20 × 10.sup.-7                               18 2.28 × 10.sup.-5 5.09 × 10.sup.-7                              22 3.01 × 10.sup.-5 3.64 × 10.sup.-7                              24 9.51 × 10.sup.-6 2.05 × 10.sup.-7                              25 1.39 × 10.sup.-5 5.86 × 10.sup.-9                              26 8.95 × 10.sup.-5 1.79 × 10.sup.-7                              28 1.39 × 10.sup.-5 2.10 × 10.sup.-8                              29 5.72 × 10.sup.-5 1.36 × 10.sup.-8                              56 8.47 × 10.sup.-5 3.36 × 10.sup.-7                              58 4.80 × 10.sup.-4 3.82 × 10.sup.-8                              64 6.19 × 10.sup.-5 2.21 × 10.sup.-8                            ______________________________________                                    

As described above, the tetrazole derivative or a salt thereof accordingto the present invention is endowed with excellent antileukotrieneactivity and anti-histaminic activity and thus is useful as a medicinefor the prevention and treatment of asthma.

What is claimed is:
 1. A tetrazole derivative, or a salt thereof,represented by formula (1): wherein ##STR8## R¹ and R², independently,represent a hydrogen atom, a hydroxyl group, a lower alkyl group, analkoxy group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6carbon atoms substituted with an alkoxy group having 1 to 6 carbonatoms, a halogen atom, a phenyl group, or a di-(C1-C4)alkylamino group;an alkanoyloxy group having 2 to 5 carbon atoms; or an alkanoyloxy grouphaving 2 to 5 carbon atoms substituted with an amino group;R³ representsa hydrogen atom, a lower alkyl group, or a lower alkyl group substitutedwith a halogen atom, an amino group, a phenyl group, or a phenyl groupsubstituted with a C1-C4 alkyl group; A represents a methyleneoxy groupor a vinylene group; Z represents an unsubstituted benzimidazole or abenzimidazole group substituted with a C1-C4alkyl group or a(C1-C4)alkoxy(C1-C4)alkyl group; and a broken line indicates that theremay be a double bond.
 2. The tetrazole derivative or a salt thereof asdefined in claim 1, wherein Z represents a benzimidazole groupsubstituted with a C1-C4 alkyl group or a (C1-C4)alkoxy(C1-C4)alkylgroup.
 3. The tetrazole derivative or a salt thereof as defined in claim1, wherein Z represents an unsubstituted benzimidazole group.
 4. Thetetrazole derivative or a salt thereof as defined in claim 1, whereinsaid lower alkyl group has 1 to 6 carbon atoms.
 5. The tetrazolederivative or a salt thereof as defined in claim 1, wherein R³ is ahydrogen atom, a methyl group, or a dimethylaminomethyl group.
 6. Thetetrazole derivative or a salt thereof as defined in claim 1, which isan addition salt of a mineral acid or an inorganic acid.
 7. The additionsalt of the tetrazole derivative as defined in claim 6, which isselected from the group consisting of hydrochlorides, hydrobromides,hydroiodides, sulfates, phosphates, benzoates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates,maleates, fumarates, tartarates, and citrates.
 8. The tetrazolederivative or a salt thereof as defined in claim 1, which is3-{1-{3-[N-(2-Ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl}tetrazolyl}-6-hydroxyquinolin-2-one,3-{1-{4-[N-(2-Ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl}tetrazolyl}-6-hydroxyquinolin-2-one,3-{2-{4-[N-(2-Ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl}tetrazolyl}-6-hydroxyquinolin-2-one,3-{2-{4-[N-(2-Ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl}tetrazolyl}-6-hydroxyquinolin-2-one,3-{1-{4-[N-(2-Ethoxyethyl)benzimidazol-2-ylmethoxy]benzyl}tetrazolyl}-6-hydroxyquinolin-2-one,3-{2-[3-(N-Methylbenzimidazol-2-ylmethoxy)benzyl]tetrazolyl}quinolin-2-oneor3-{1-[3-(N-Methylbenzimidazol-2-ylmethoxy)benzyl]tetrazolyl}quinolin-2-one9. A composition, comprising the tetrazole derivative or a salt thereofas defined in claim 1, and a pharmaceutically acceptable carrier. 10.The composition of claim 9, which is in the form of a tablet, capsule,granule, powder, syrup or suppository.
 11. A method of treating asthma,which method comprises administering to a patient in need thereof aneffective amount of a tetrazole derivative or a salt thereof asdescribed in claim 1.